Morphological variability may limit single-cell specificity to electric field stimulation

Non-invasive brain stimulation techniques are widely used for manipulating the behaviour of neuronal circuits and the excitability of the neurons therein. While the usage of these techniques is widely studied at the meso- and macroscopic scales, less is known about the specificity of such approaches at the level of individual cells. Here we use models based on the morphologies of real pyramidal and parvalbumin neurons from mouse primary visual cortex created by the Allen Institute for Brain Science to explore the variability and evoked response susceptibility of different morphologies to uniform electric fields. We devised a range of metrics quantifying various aspects of cellular morphology, ranging from whole cell attributes to net compartment length, branching, diameter to orientation. In supporting layer- and cell-type specific responses, none of these physical traits passed statistical significance tests. While electric fields can modulate somatic, dendritic and axonal compartments reliably and subtype-specific responses could be observed, the specificity of such stimuli was blurred by the variability in cellular morphology. These null results suggest that morphology alone may not account for the reported subtype specificity of brain stimulation paradigms, and question the extent to which such techniques may be used to probe and control neural circuitry. Author summaryOver the last several decades there has been increased interest in the efficacy of non-invasive brain stimulation, particularly in determining the limits of specificity of such techniques. Despite this growing area of research, much remains unknown about the interactions of non-invasive techniques with neurons at the single-cell level, notably the importance of morphology to these interactions. We make use of detailed single-neuron models and simulate them in a uniform electric field and demonstrate that the high variability in neuron morphologies may limit how specifically single neurons can be targeted non-invasively. We confirmed this for neuron morphology characteristics at macro- and meso- scales and at varied orientations. Our work suggests that previously reported subtype specificities in non-invasive frameworks are not accounted for by considering only morphological factors.